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Molecular Glue Degraders of TEM β‐Lactamases by Periplasmic Protease DegP

Year: 2026
Type: article
Abstract: Antimicrobial resistance is one of the most serious challenges to global health, yet the development of new molecules with novel mechanisms of action to combat resistance is lacking. In this study, we report the discovery of molecular glues that recruit TEM-family β-lactamases to the bacterial protease DegP for degradation. β-Lactamase inhibitor tazobactam was found to accelerate degradation of TEM β-lactamases by DegP, which was further enhanced by linkerless incorporation of dipeptide motifs enriched among DegP substrates. The resulting molecular glue degraders showed improved synergy with β-lactam piperacillin against resistant Escherichia coli compared to tazobactam, as well as good pharmacokinetic properties for oral dosing. Collectively, this work establishes periplasmic targeted protein degradation as a promising new mechanism for combating β-lactamase resistance.
DOI: 10.1002/ange.3138186
Authors: Emilia K. Taylor, Patricia Santos Barbosa, Tarini Kadambi, Frederik Eisele, Yiqiao Wang, Elisabete C. C. M. Moura, Timothy R. Walsh, Georgia L. Isom, Thomas Lanyon‐Hogg
Language: English
Open Access status: hybrid
Estimated APC paid: $5,790
Funders: Wellcome Trust, Royal Society, Royal Society of Chemistry, University of Oxford, European Commission, Korea Advanced Institute of Science and Technology, HORIZON EUROPE Framework Programme, Medical Research Council, European Research Council
Awards: Unlocking new targets to combat antimicrobial resistance through chemical biology, High-throughput development of bacterial PROTACs, G2697625627, Investigating new systems for integrity of the bacterial outer membrane, Chemistry in Cells – New Technologies to Probe Complex Biology and Medicine., Chemistry in Cells – New Technologies to Probe Complex Biology and Medicine.
OpenAlex ID: W7147184578
FWCI: 1.932
Cites: 31
Cited by: 1
Related to: 10